Synthesis of beta,beta-di-alkyl pyrrolidines

ABSTRACT

A PROPARGYL IS SEMI-HYDROGENATED TO THE CORRESPONDING ALLYL MALONATE WHICH IS HYDROLYZED TO THE MALONIC ACID. DECARBOXYLATION OF THE ACID IS READILY EFFECTED BY HEAT, RESULTING IN THE PRODUCTION OF AN UNSATURATED ACID WHICH IS READILY CYCLIZED TO A 4-METHYL-GAMMA LACTONE. THE LATTER IS CONVERTED TO 2-METHYL-BETA,BETA-SUBSTITUTED PYRROLIDINES VIA THE CORRESPONDING 5-METHYL-2-PYRROLIDONES.

United States Patent O 3,567,726 SYNTHESIS OF fl,;8-DI-ALKYLPYRROLIDINES Robert D. Dillard and Nelson R. Easton, Indianapolis, Ind.,assignors to Eli Lilly and Company, Indianapolis, Ind. No Drawing.Application July 12, 1967, Ser. No. 652,690, now Patent No. 3,452,015,dated June 24, 1969, which is a continuation-in-part of application Ser.No. 311,305, Sept. 25, 1963. Divided and this application Dec. 18, 1968,Ser. No. 810,875

Int. Cl. G07d 51/76 US. Cl. 260-250 1 Claim ABSTRACT OF THE DISCLOSURE Apropargyl is semi-hydrogenated to the corresponding allyl malonate whichis hydrolyzed to the malonic acid. Decarboxylation of the acid isreadily effected by heat, resulting in the production of an unsaturatedacid which is readily cyclized to a 4-methyl-gamma lactone. The latteris converted to Z-methyl-beta,beta-substituted pyrrolidines via thecorresponding S-methyI-Z-pyrroliclones.

CROSS REFERENCE This application is a division of SN. 652,690, filedJuly 12, 1967, now Pat. No. 3,452,015, issued June 24, 1969, which inturn is a continuation-in-part of application Ser. No. 311,305, filedSept. 25, 1963, now abandoned.

BACKGROUND OF THE INVENTION Prior art methods of synthesizingpyrrolidines include the hydrogenation of a pyrrole, as exemplified inAndrews and McElvain, J. Am. Chem. Soc. 51, 887 (1929), reduction of thecorresponding pyrrolidone as exemplified in the work of Pernot et al.,Bull. Soc. Chim. Fr. 1953, 324, the reduction of a succinimide asexemplified in Rice et al., J. Org. Chem. 19, 884 (1959) and by theself-condensation of a fi-haloalkylamine. This last method has beenapplied to the preparation of fl-substituted pyrrolidines by Brown andvan Gulick, I. Am. Chem. Soc. 77, 1083 (1955).

SUMMARY The process provided by this invention is a multi-step process,the first step of which involves the hydrolysis of a propargyl-malonateto the corresponding dicarboxylic acid which is then cyclized to form acarboxyhydroxypentanolactone. Opening of the lactone ring with theconcomitant decarboxylation of one of the carboxyl groups yieldsdirectly -a y-keto acid. This 'y-keto acid upon reaction with ammoniaforms a 'methylenepyrrolidone. Hydrogenation of this compound, firstcatalytically, and then with a chemical reducing agent such as lithiumaluminum hydride, yields the desired u-methyl-,B,fl-di-alkyl-substitutedpyrrolidine.

3,567,726 Patented Mar. 2, 1971 ice The above process can be bettervisualized by reference to Reaction Scheme 1 below:

R and R, when taken separately, are members of the group consisting of C-C alkyl and C -C cycloalkyl;

R and R, when taken together with the carbon atom which they areattached, represent a C -C cycloalkyl p;

R" is a member of the group consisting of hydrogen, C -C alkyl, C -Ccycloalkyl, monocyclic aromatic and monocyclic aromatic-substituted C -Calkyl; and,

Alk is aC -C alkyl group.

According to the above reaction scheme, a propargylsubstituted malonicester (I) is hydrolyzed under mild basic conditions to yield thecorresponding dicarboxylic acid (II). Treatment of the di-acid (II) withbase results in the formation of a hydroxycarboxylactone (IH). Uponheating, the lactone ring of this compound opens with the concomitantloss of carbon dioxide to give a fifi-disubstituted levulinic acid (IV),treatment of which with ammonia results in the formation ofamethylenepyrrolidone (V). Catalytic hydrogenation of the pyrrolidoneusing a noble metal catalyst such as platinum oxide yields thecorresponding a-methyl-B,[3-di-substituted pyrrolidone (VI). These lasttwo operations can be telescoped into a single process whereby the ketoacid (IV) is hydrogen ated over a metal catalyst such as Raney nickel inthe presence of ammonia to yield the a-methylpyrrolidone directly.Finally, reduction of the u-methyl-fi,fl-di-substituted pyrrolidone, forexample with a metal hydride reducing agent such as lithium aluminumhydride, yields the desired fifi-di-alkyl-substituted pyrrolidine (VI).

3 An alternative synthetic pathway is provided by this invention for thepreparation of the 5,}9-di-substituted pyrrolidone (VI). This pathway isset forth in Reaction Scheme 2 below:

Reaction Scheme 2 wherein R, R, R", and alk have the same meaning ashereinabove.

According to Reaction Scheme 2, a propargyl-substituted di-alkylmalonate (I in Reaction Scheme 1) is semi-hydrogenated catalyticallyusing a palladium catalyst to yield the corresponding allyl-substituteddi-alkyl malo nate (IX). Basic hydrolysis of this compound yields thecorresponding allyl-substituted malonic acid (X). [This latter compoundcan also be prepared by an alternative procedure which involves thesemi-hydrogenation of the propargyl-substituted malonic acid (II fromReaction Scheme 1)] Decarboxylation of the malonic acid is readilyeffected by heat, resulting in the production of an unsaturated acid(XI), which readily cyclizes to yield the corresponding lactone (XII).Treatment of the lactone (XII) with ammonia yields the desired@fi-di-alkyl-substituted pyrrolidone, (VIII).

In the above reaction schemes, when R, R, and R" represent C -C alkyl orC -C cycloalkyl or R and R taken together, form a C -C cycloalkyl group,they can be illustratively: methyl, ethyl, n-propyl, isopropyl, sec.--butyl, n-butyl, isobutyl, iso-amyl, t-amyl, n-amyl, 2-pentyl, 3-pentyl,3-methyl-2-butyl, 2-hexyl, 1-hexyl, 3-hexyl, 4- methyl-Lpentyl, 3 methyll pentyl, 3-methyl-2-pentyl, neopentyl, 3,3-dimethyl-l-butyl,3,3-dimethyl-l pentyl, 3,3,4-trimethyl-1-pentyl, 2,2,4-trimethyl 1pentyl, 2,4,4- dimethyl-Z-pentyl, iso-octyl, isoheptyl, n-heptyl,2-heptyl, 3-heptyl, 4-heptyl, 2-octy1, 3-octyl, 4-octyl, cyclopropyl,cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cyclooctyl,3-methylcyclohexyl, 2,2-dimethylcyclopentyl, and the like. R" canrepresent a monocyclic aromatic group or a monocyclic aromaticsubstituted C -C alkyl group. The term monocyclic aromatic includes suchradicals as phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Z-thienyl,3-thienyl, 2- furyl, 3-furyl, 2-pyr-imidyl, 4-pyrimidyl, 2-pyrrolyl, 2-pyrazinyl, 3-pyrazinyl, S-thiazolyl, Z-imidazolyl, S-tetrazoyl,3-pyrazolyl, 4-isoxazolyl and 4-imidazolyl. Each of the above groups isderived from an organic monocyclic radical which satisfies the standardcriteria for aromaticity. These criteria are (1) that the ring systemcontain (4N+2) pi electrons and (2), in the case of bicyclic systems,that the rings are planar. These concepts of aromaticity are fully setforth in articles by Wilson Baker, Perspectives in Organic Chemistry,1956; by Robert Breslow, On Aromatic Character, Chemistry andEngineering News, page 90, June 28, 1965; and by Hiickel in histreatise, Theoretische Grundlagen der Organischen Chemie, 2. Aufiage, 1.Band, Akademische' Verlagsgesellschaft m.b.H., Leipzig 1934. Inaddition, the term monocyclic aromatic includes any of the above ringsystems when substituted with a standard substituting group such aslower alkyl, lower alkoxy, amino, lower alkylamino, dilower alkylamino,halogen, nitro, and the like. In the above substituent groups, the termlower alkyl is meant to include those radicals having from 1-3 carbonatoms in the alkyl chain. The term halogen" includes all members of theseventh main group of the periodic system. In addition, any givenaromatic ring can contain more than one of the above substitutinggroups. The following radicals will serve to illustrate substitutedaromatic groups falling within the definition of the term as usedherein; 2- chloro 3 furyl, 2 chloro-S-thienyl, o-tolyl,p-dimethylaminophenyl, 4-amino-2-pyridyl, p-trifluoromethylphenyl,m-(di-n-propylamino)phenyl, p-anisyl, m-ethoxy-p-bromophenyl,p-iodophenyl, 3-n-propoxy-2-pyridyl, p-isopropoxyphenyl, 2,4dimethylphenyl, 3,4 methylenedioxyphenyl, 2-chloro-4-nitrophenyl, andthe like. Groups illustrating the scope of R when it is monocyclicaromatic are set forth above. Groups illustrating the scope of R when itrepresents monocyclic aromatic substituted C C include benzyl,phenethyl, 3-(2-phenyl)octyl, furfuryl, 3-(2- pyridyD-n-pentyl,Z-pyrimidylmethyl, 2-methyl-2-phenylethyl, 3 (5-thiazolyl)-n-propyl,4-(2-imidazolyl)isoheptyl, 6(3-pyrazolyl)-n-hexyl, 2-(4-imidazolyl)ethyland the like.

Considering Reaction Scheme 1 above in more detail, the hydrolysis of apropargyl-substituted malonic ester (I) usually requires only mildalkaline conditions for its completion. However, the reaction wherebythe malonic acid (II) or malonic ester (I) is converted to the lactone(III) whereby the acetylenic bond is hydrated, requires somewhat morestringent conditions, for example, refluxing overnight with 10 percentsodium hydroxide. The resulting lactone is customarily isolated byacidifying the reaction mixture and extracting the lactone with awaterimmiscible organic solvent. The conversion of the lactone to thesubstituted levulinic acid (IV) takes place under standarddecarboxylation reaction conditions; that is to say, the lactone issimply heated until the evolution of carbon dioxide ceases, at whichtime' the reaction is substantially complete. An organic solvent can beused here if desired. Conversion of the levulinic acid to themethylenepyrrolidone (V) is usually carried out in an autoclave using anexcess of ammonia. The reduction of the methylene group to a methylgroup, Whether carried out in an atmosphere of hydrogen only or withadded ammonia, normally requires only the use of a low pressurehydrogenation apparatus and a noble metal catalyst such as platinumoxide, palladium-on-carbon, etc. It is possible, however, to employ highpressure hydrogenation conditions using a less active catalyst such asRaney nickel. When the levulinic acid is converted directly to themethylpyrrolidone (VI), we prefer to employ high pressure hydro genationconditions with an excess of ammonia present and Raney nickel as acatalyst. Finally, the reduction of the methylpyrrolidone (VI) to thecorresponding pyrrolidine (VII) is preferably carried out using lithiumaluminum hydride in an ethereal solvent. Other metal hydride reducingagents such as sodium aluminum hydride, sodium borohydride, and thelike, can also be employed.

Considering Reaction Scheme 2 in more detail, the reduction of thepropargyl-substituted malonic ester (I) in readily carried out using lowpressure hydrogenation conditions and a noble metal catalyst such aspalladiumon-carbon or platinum oxide. The hydrolysis of theallylsubstituted malonic ester (IX) thus formed to the correspondingacid is accomplished by using about 10 percent alkali and the allylmalonic acid (X) is obtained from the hydrolysis mixture byacidification followed by extraction of the acid into a water-immiscibleorganic solvent. Decarboxylation of the allyl malonic acid (X) to yieldan unsaturated acid (XI) is carried out by simply heating the acid,either alone or in an inert solvent. Conversion of the acid (XI) intothe corresponding lactone (XII) is readily accomplished by treating theunsaturated acid with a mineral acid such as concentrated sulfuric acidfor a short period of time and then extracting the resulting lactoneinto ether. Conversion of the lactone of the correspondingu-methyl-Z-pyrrolidone is brought about by heating the lactone in anautoclave with an excess of aqueous ammonia.

The substituted pyrrolidines which are the ultimate products of thenovel processes of this invention, containing as they do two alkylsubstituents on a carbon 3 to the ring nitrogen, represent a class ofcompounds which have been synthesized only with difliculty in the past.The large variety of substituents which R and R can represent also lendsa versatility and scope to the process of this invention, a versatilityand scope not found in those processes of the prior art useful for thesynthesis of {Mi-dialkyl pyrrolidines. The pyrrolidines themselves, ofcourse, are useful in the same ways that the parent compound and itsmono-alkyl substitution products have been used in the past, such asdrug intermediates, solvents, corrosion inhibitors, and the like.

This invention is further illustrated by the following 7 specificexamples:

EXAMPLE 1 2-carboxy-3 ,3-dimethyl-4-hydroxy-4-pentanolactone A mixtureof 17 g. of diethyl 1,1-dimethylpropargylmalonate [prepared by themethod of O. K. Behrens et al., J. Biol. Chem. 175, 788 (1948)] and 200ml. of percent sodium hydroxide was refluxed overnight, and was thenevaporated to dryness in vacuo. The resulting residue was dissolved inwater. The aqueous solution was cooled to about C. and was made acidicwith 12 N hydrochloric acid, thus forming 2-carbox-3,3-dimethyl-4-hydroxy-4-pentanolactone which was extracted from the acidic aqueouslayer by ether followed by chloroform. The organic extracts wereseparated, and the organic solvent was removed by evaporation in vacuo.Crystallization of the resulting residue from a mixture of ether andhexane yielded 2-carboxy-3,3-dimethyl 4 hydroxy-4- pentanolactonemelting at about 118-122" C.

Analysis.Calcd. (percent): C, 51.06; H, 6.43. Found (percent): C, 51.09;H, 6.37.

Following the above procedure, Z-carboxy 2 ethyl-3,3-dimethyl-4-hydroxy-4-pentanolactone was prepared from diethyl ethyl 1,1dimethylpropargylmalonate. The compound melted at about 152153 C.

Analysis.-Calcd. (percent): C, 55.54; H, 7.64. Found (percent): C,55.60; H, 7.63.

EXAMPLE 2 3,3-dimethyllevulinic acid Twenty-five grams of2-carboxy-3,3-dimethyl-4-hydroxy-4-pentanolactone were heated at 155 C.for one hour thus forming 3,3-dimethyllevulinic acid which was purifiedby distillation. The compound boiled at about 79 C./0.02 mm. Hg.

Analysis.-Calcd. (percent): C, 58.31; H, 8.39. Found (percent): C,58.41; H, 8.54.

Following the above procedure, 2-ethyl-3,3-dimethyllevulinic acid wasprepared from 3-carboxy-3-ethyl-4,4,5- trimethyl-5-hydroxy-2-furanone.It boiled in the range 84- 85 C./0.1 mm. Hg.

Analysis.Calcd. (percent): C, 62.76; H, 9.36. Found (percent): C, 62.66;H, 9.36.

EXAMPLE 3 4,4-dimethyl-5-methylene-2-pyrrolidone A mixture of 26 g. of3,3-dimethyllevulinic acid, 50 ml. of ethanol, and an excess of ammoniawas heated in an autoclave at about 185 C. for about 5 hours. Thevolatile constituents of the mixture were removed in vacuo and theresulting residue comprising 4,4-dimethyl-S-methylene- Z-pyrrolidone waspurified by distillation. The compound boiled in the range 110-115 C./4mm. Hg. The distillate solidified upon standing, yielding crystalline4,4-dimethyl- S-methyIene-Z-pyrrolidone which melted at about 72-74 C.after recrystallization from pentane.

Analysis.-Calcd. (percent): C, 67.17; H, 8.85. Found (percent): 66.91;H, 8.82.

6 EXAMPLE 4 4,4,5 -trimethyl-2-pyrrolidone A mixture of 70 g. of3,3-dimethyllevulinic acid, 10 g. of Raney nickel, 500 ml. of ethanoland an excess of ammonia was heated in a high pressure hydrogenationbomb at about C. for about 5 hours at a hydrogen pressure of 2000 p.s.i.The catalyst was removed by filtration and the ethanol and ammonia wereremoved from the filtrate by evaporation in vacuo. The resultingresidue, comprising 4,4,5-trimethyl-2-pyrrolidone, was purified by,distillation; the compound distilled at about 85 C./0.2

mm. Hg.

Analysis.Calcd.: N, 11.01%. Found: N, 10.94%.

4,4,5 trimethyl-2-pyrrolidone was also prepared from the correspondingmethylene compound of Example 3 in the following manner: 5 g. of4,4-dimethyl-5-methylene- 2-pyrrolidone and 0.5 g. of 5 percentpalladium-on-carbon were mixed with ml. of ethanol, and the mixture washydrogenated at 40 p.s.i. until the theoretical quantity of hydrogen hadbeen absorbed. The catalyst was removed by filtration and the filtrateevaporated to dryness in vacuo. The residue, comprising 4,4,5-trimethyl-Z-pyrrolidone, was purified by distillation as before.

EXAMPLE 5 2,3,3-trimethylpyrrolidine Four g. of4,4,S-trimethylpyrrolidone were reduced by means of 2.3 g. of lithiumaluminum hydride in 250 ml. of di-ethyl ether. After completion of thereaction, the reaction mixture was treated with 20 percent aqueoussodium hydroxide to destroy the excess reducing agent. The ether layerwas separated, dried, and the ether removed by evaporation in vacuo. Theresulting residue was distilled and 2,3,3-trimethylpyrrolidine boiled atabout 65 C./85 mm. Hg.

The hydrochloride salt of 2,3,3-trimethylpyrrolidine was prepared bydissolving the free base in ethyl acetate and then saturating theresulting solution with gaseous hydrogen chloride.2,3,3-trimethylpyrrolidine hydrochloride, thus prepared, melted at about148150 C. after recrystallization from ethyl acetate.

Analysis.-Calcd. (percent): C, 56.17; H, 10.78. Found (percent): C,56.03; H, 10.82.

EXAMPLE 6 Di-ethyl 1,l-dimethylallylmalonate Two hundred twenty-sixgrams of di-ethyl 1,1-dimethylpropargylmalonate were hydrogenated inhexane solution at a hydrogen pressure of 40 p.s.i. over a 5 percentpalladium-on-carbon catalyst. After the theoretical quantity of hydrogenhad been absorbed, the catalyst was removed by filtration and thefiltrate was concentrated by evaporation in vacuo. The resulting residueconsisted of di-ethyl 1,l-dimethylallylmalonate which was purified bydistillation. Di-ethyl 1,l-dimethylallylmalonate distilled in the range52-54 C./0.05 mm. Hg.

Analysis.Calcd. (percent): C, 63.13; H, 8.83. Found (percent): C, 63.06;H, 8.73.

EXAMPLE 7 1,1-dimethylallylmalonic acid A flask containing g. ofdi-ethyl 1,1-dimethylallylmalonate, 128 g. of sodium hydroxide, and 1000ml. of water was heated at refluxing temperature overnight. The reactionmixture was then concentrated by evaporation in vacuo and the resultingconcentrate, upon acidification with 12 N hydrochloric acid, yieldedabout 1500 ml. of a clear solution. 1,1-dimethylallylmalonic acidcrystallized from the solution on standing and melted at about 104- 106C., after recrystallization from a mixture of benzene and ethyl acetate.

Analysis.Calcd. (percent): C, 55.80, H, 7.03. Found (percent) C, 55.54;H, 7.12.

7 EXAMPLE 8 3,3-dimethyl-4-pentenoic acid Eighty-five grams of1,l-dimethylallylmalonic acid were heated at about 157 C. for threehours, thus forming 3,3- dimethyl-4-pentenoic acid by decarboxylation.The reaction mixture was filtered and the filtrate was distilled. 3,3-dimethyl-4-pentenoic acid boiled in the range 4748 C./ 0.1 mm. Hg; n=1.423.

Analysis.Calcd. (percent): C, 65.59; H, 9.44. Found (percent): C, 65.55;H, 9.60.

EXAMPLE 9 3 ,3-dimethyl-4-pentanolactone Ten grams of3,3-dimethyl-4-pentenoic acid were stirred with 50 ml. of 18 M sulfuricacid for about 10 minutes, and the acidic solution was then poured over200 g. of ice. 3,3-dimethyl-4-pentanolactone formed in the abovereaction was extracted therefrom with ether. The ether solution wasseparated and dried, and the ether removed by evaporation in vacuo.Distillation of the residue yielded 3,3- dimethyl-4-pentanolactoneboiling at about 50 C./ 0.5 mm. Hg.

Analysis.Calcd. (percent): C, 65.59; H, 9.44. Found (percent): C, 65.53;H, 9.71.

EXAMPLE 10 4,4,S-trimethyl-3-phenylpyrrolidone 2-phenylmalonic ester wasalkynylated with 3-chloro-3- methyl-l-butyne by the method of O. K.Behrens et al. (loc. cit.) to yield diethyl 2-(1,l-dimethylpropargyl)-2- phenylmalonate. This compound was converted bythe method of Example 1 to 2-carboxy-2-phenyl-3,3-dirnethyl-4-hydroxy-4-pentanolactone which spontaneously decarboxylated to yield3,3 dimethyl-2-phenyllevulinic acid. M.P.=141-143 C.

Analysis.-Calcd. (percent): C, 70.88; H, 7.32. Found (percent): C,70.83; H, 7.44.

Reductive ammination of the latter compound by the procedure of Example4 yielded 4,4,5-trirnethyl-3-phenylpyrrolidone, M.P.=198-200 C.

AnaIysis.-Calcd. (percent): C, 76.81; H, 8.43; N, 6.84. Found (percent):C, 77.00; H, 8.44; N, 6.95.

4,4,5-trimethyl-3-phenylpyrrolidone thus prepared is readily reduced bythe process of Example to 2,3,3-trimethyl-4-phenylpyrrolidine.

3,3-dimethyl-Z-phenyllevulinic acid can also be converted by theprocedure of Example 3 to 4,4-dimethyl-5- methylene-3-phenylpyrrolidone,which compound can in turn be reduced to the corresponding4,4,5-trimethyl derivative.

EXAMPLE 11 3-phenethyl-4,4,5-trimethyl-2-pyrrolidone 3-phenethylmalonicester was alkynylated with 3-chloro- 3-methyl-1-butyne by the method ofO. K. Behrens et al. (loc. cit.) to yield diethyl2-(1,1-dimethylpropargyl)-2- phenethylmalonate. This compound wasconverted by the method of Example 1 to2-carboxy-3-phenethyl-3,3-dimethyl-4-hydroxy-4-pentanolactone, whichcompound was in turn converted by the method of Example 2 to3,3-dimethyl-2-phenethyllevulinic acid. Reductive ammination of thelatter compound by the procedure of Example 4 yielded3-phenethyl-4,4,5-trimethyl-Z-pyrrolidone.

3-phenethyl 4,4,5 trimethyl-2-pyrrolidone thus prepared is readilyreduced by the process of Example 5 to2,3,3-trimethyl-4-phenethylpyrrolidine.

3,3-dimethyl-2-phenethyllevulinic acid can also be converted by theprocedure of Example 3 to 4,4-dimethyl-5-methylene-3-phenethylpyrrolidone, which compound can in turn be reducedto the corresponding 4,4,5-trimethyl derivative.

8 EXAMPLE l2 3-benzyl-4,4,5-trimethyl-2-pyrrolidone 2-benzylmalonicester was alkynylated with 3-chloro-3- methyl-l-butyne by the method ofO. K. Behrens et al. (loc. cit.) to yield diethyl2-(1,l-dimethylpropargyl)-2 benzylmalonate. This compound was convertedby the method of Example 1 to 2-carboxy-2-benzyl-3,3-dimethyl-4-hydroxy-4-pentanolactone, M. P.=147 C.

Analysis.-Calcd. (percent): C, 64.73; H, 6.52. Found (percent): C,64.57; H, 6.59.

The pentanolactone was in turn converted by the method of Example 2 to3,3-dimethyl-Z-benzyllevulinic acid. Reductive ammination of the lattercompound by the procedure of Example 4 yielded3-benzyl-4,4,5-trimethyl-2- pyrrolidone.

3-benzyl-4,4,5-trimethyl 2 pyrrolidone thus prepared is readily reducedby the process of Example 5 to 2,3,3-trimethyl-4-benzylpyrrolidine.

3,3-dimethyl-2-benzyllevulinic acid can also be converted by theprocedure of Example 3 to 4,4-dimethyl-5- methylene-Z-benzylpyrrolidonewhich compound can in turn be reduced to the corresponding4,4,5-trimethyl derivative.

EXAMPLE l3 3-(Z-pyridylethyl)-4,4,5-trimethyl-2-pyrrolidone2-(2-pyridylethyl)malonic ester was alkynylated with3-chloro-3-methyl-l-butyne by the method of O. K. Behrens et al. (loc.cit.) to yield diethyl 2-(1,1-dimethylpropargyl)2-(2-pyridylethyl)malonate. This compound wasconverted by the method of Example 1 to 2-carboxy-2-(Z-pyridylethyl)3,3-dimethyl 4 hydroxy-4-pentanolactone, whichcompound was in turn converted by the method of Example 2 to3,3-dimethyl-2-(Z-pyridylethyl) levulinic acid. Reductive ammination ofthe latter compound by the procedure of Example 4 yielded3-(2-pyridylethyl)-4,4,5-trimethyl-2-pyrrolidone.

3 (2 pyridylethyl)-4,4,5-trimethyl-2-pyrrolidone thus prepared isreadily reduced by the process of Example 5 to2,3,3-trimethyl-4-(Z-pyridylethyl)pyrrolidine.

3,3-dimethyl-2-(2-pyridylethyl)levulinic acid can also be converted bythe procedure of Example 3 to 4,4-dimethyl-5-methylene-3- Z-pyridylethylpyrrolidone which compound can in turn be reduced to the corresponding4,4,5-trimethyl derivative.

EXAMPLE 14 3- (Z-thienylmethyl)-4-4,5-trimethyl-2-pyrrolidone2-(2-thienylmethyl)malonic ester was alkynylated with3-chloro-3-methyl-1-butyne by the method of O. K. Behrens et al. (loc.cit.) to yield diethyl 2-(1,1-dimethylpropargyl)-2-(2-thienylmethyl)malonate. This compound wasconverted by the method of Example 1 to 2-carboxy- 2 (2thienylmethyl)-3,3-dimethyl-4-hydroxy4-pentanolactone, which compoundwas in turn converted by the method of Example 2 to3,3-dimethyl-2-(Z-thienylmethyl)levulinic acid. Reductive ammination ofthe latter compound by the procedure of Example 4 yielded 3-(2-thienylmethyl)-4,4,S-trimethyl-2-pyrrolidone.

3- Z-thienylmethyl -4,4,5-trimethyl-2-pyrrolidone thus prepared isreadily reduced by the process of Example 5 to 2,3 ,3 -trimethyl-4-Z-thienylmethyl pyrrolidine.

3,3-dimethyl-2-(Z-thienylmethyl)levulinic acid can also be converted bythe procedure of Example 3 to 4,4-dimethyl 5 -methylene-3-Z-thienylmethyl -2-pyr rolidone, which compound can in turn be reducedto the corresponding 4,4,5-trimethyl derivative.

The procedures of Examples 15 above can be used to prepare the followingcompounds:

3-(4-pyridyl)-4,4,5-trimethyl-2-pyrrolidone Starting material: diethyl2-(1,1-dimethylpropargyl)-2- (4-pyridyl) malonate Intermediates:

9 2 carboxy-2-(4-pyridyl)-3,3-dimethyl-4-hydroxy-4- pentanolactone3,3-dimethyl-2-(4-pyridyl)levulinic acid 4,4-dimethyl--methylene-3-(4-pyridyl) pyrrolidone 3-( 3-pyrazolyl) -4,4,S-trimethyl-Z-pyrrolidoneStarting material: diethyl 2-(1,1-dimethylpr0pargyl)-2- (3-pyrazolyl)malonate Intermediates:

2 carboxy-2-(3-pyrazolyl)-3,3-dimethyl-4-hydroxy- 4-pentanolactone3,3-dimethyl-2-(3-pyrazolyl)levulinic acid 4,4 dimethyl5-methylene-3-(3-pyrazolyl)pyrrolidone 3-(5-thiazoly1)-4,4,S-trirnethyl-Z-pyrrolidone Starting material: diethyl2-(1,1-dimethylpropargyl)-2- (5-thiazolyl)malonate Intermediates 2carboxy-2-(S-thiazolyl)-3,3-dimethyl-4-hydroxy- 4-pentanolactone3,3-dimethyl-2-(5-thiazolyl)levulinic acid 4,4dimethyl-5-methylene-3-(5-thiazolyl)-2-pyrrolidone In the aboveexamples, there are set forth a number of classes of intermediates,including 2-carboxy-2,3,3-trisubstituted-4-phentanolactones and4,4-di-substituted-5- methylene-2-pyrrolidones. Both of these classes ofintermediates are useful in the processes of this invention, theultimate products of which are 3,;3-di-alkyl-substituted pyrrolidineswhose utility has been set forth above.

We claim:

1. The process which comprises semi-hydrogenating in the presence of anoble metal catalyst a propargyl-substituted di-alkylrnalonaterepresented by the following for mula:

RC (0 0 Oalk): R-(E-CECH wherein R and R, when taken separately, aremembers of the group consisting of C -C alkyl and C -C cycloalkyl;

R and R, when taken together with the carbon atom to which they areattached, form a C -C cycloalkyl radical;

R" is a member of the group consisting of hydrogen, C -C alkyl, C -Ccycloalkyl, monocyclic aromatic and monocyclic aromatic-substituted C -Calkyl; and

alk is a C -C alkyl group;

thus forming an allyl-substituted malonate represented by the followingformula:

wherein R, R, R", and alk have the same meaning as hereinabove;

hydrolyzing said allyl malonate with base to yield the correspondingmalonic acid represented by the following formula:

decarboxylating said malonic acid with heat to form an unsaturated acidof the following formula:

R"CHCOOH R- -GH=CH wherein R, R, and R" have the same meaning ashereinabove;

treating said unsaturated acid with mineral acid to form a lactonerepresented by the following formula:

wherein R, R, and R" have the same meaning as hereinabove,

treating said lactone with ammonia to yield the correspondingpyrrolidone represented by the following formula:

wherein R, R, and R" have the same meaning as hereinabove; and,

then reducing said pyrrolidone with a metal hydride reducing agent toyield the corresponding 18,;9-di-alkyl-substituted pyrrolidinerepresented by the following formula: I?! R CH-OH2 wherein R, R, and Rhave the same meaning as hereinabove.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner

